Type 1 (insulin-dependent) diabetes is due to the selective, autoimmune-mediated destruction of beta cells in the pancreatic islets of Langerhans, with consequent insulin deficiency and hyperglycemia. Most people with type 1 diabetes must rely on exogenous insulin for their survival, at great daily inconvenience and at long-term risk of complications associated with imperfect blood glucose control. Now that individuals at risk for type 1 diabetes can be identified, a major goal is the design of intervention therapies to prevent diabetes. The aims of the proposal are to: a) establish if transfer of proinsulin transgenic NOD BM prevents diabetes in non-transgenic NOD recipients; b) develop BM transfer protocols to prevent diabetes that require minimum or no myeloablative conditioning of the recipient; c) determine if transfer of diabetes protection can be achieved once islet autoimmunity is established, and d) define the APC and mechanisms responsible for diabetes prevention. This proposal is based on the principle that HSC containing a transgene can be used as a vehicle for gene expression and tolerance induction by hematopoietically derived APC.